DMID Interventional Protocol TemplateVersion 5.0
25 March 2011
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PREFACE
This document is the DMID protocol template, which is required for developing DMID-sponsored clinical research protocols. Note that instructions and explanatory text are indicated by italics and should be replaced in your protocol document with appropriate protocol-specific text. Section headings and template text formatted in regular type should be included in your protocol document as provided in the template. Text should be formatted using Body Text style. Bulleted lists should be formatted using Bullet (listing) style.
This template attempts to provide a general format applicable to all clinical trials evaluating an investigational product. Where specific examples are provided, they are often from the vaccine area.
Throughout this protocol template, there may be subject headings that do not apply to your particular study. In such instances, please write “not applicable.”
In places where the information is duplicative, it is acceptable to reference another section rather that repeating the information.
Refer questions regarding use of this protocol template to the appropriate DMID Protocol Champion or Clinical Affairs Specialist.
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DMID Interventional Protocol TemplateVersion 5.0
25 March 2011
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TITLE
DMID Protocol Number:
DMID Funding Mechanism: (e.g., grant #, contract #)
Pharmaceutical Support Provided by: (if applicable)
Other Identifying Numbers:
IND Sponsor: (if applicable. Do not include IND number)
Principal Investigator:
DMID Protocol Champion:
DMID Medical Monitor:
DMID Clinical Affairs Specialist:
DMID Regulatory Affairs Specialist: (if applicable)
Draft or Version Number: (Refer to DMID SOP for assigning version numbers)
Day Month Year
(Write out the month and use international date format, e.g., 23 January 2004)
This template is adapted from the ICH guidance document E6 (Good Clinical Practice), Section6.
Statement of Compliance
Refer to:
Provide a statement that the trial will be conducted in compliance with the protocol, International Conference on Harmonisation E6: Good Clinical Practice: Consolidated Guideline (ICH E6) and the applicable regulatory requirements.
Example text:
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the following (use applicable regulations depending on study location and sponsor requirements; samples follow):
- United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312)
- ICH E6; 62 Federal Register 25691 (1997)
- NIH Clinical Terms of Award
All key personnel (all individuals responsible for the design and conduct of this study) have completed Human Subjects Protection Training.
Signature Page
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable US federal regulations and ICH guidelines.
Site Investigator:*Signed: / Date:
Name
Title
* The protocol should be signed by the local investigator who is responsible for the study implementation at his/her specific site; i.e., if Investigational New Drug study, the individual who signs the Form FDA 1572.
Table of Contents
Page
Statement of Compliance
Signature Page
Table of Contents
List of Abbreviations
Protocol Summary
1Key Roles
2Background Information and Scientific Rationale
2.1Background Information
2.2Rationale
2.3Potential Risks and Benefits
2.3.1Potential Risks
2.3.2Known Potential Benefits
3Objectives
3.1Study Objectives
3.2Study Outcome Measures
3.2.1Primary Outcome Measures
3.2.2Secondary Outcome Measures
4Study Design
4.1Substudies (if applicable)
5Study Enrollment and Withdrawal
5.1Subject Inclusion Criteria
5.2Subject Exclusion Criteria
5.3Treatment Assignment Procedures
5.3.1Randomization Procedures
5.3.2Masking Procedures
5.3.3Reasons for Withdrawal
5.3.4Handling of Withdrawals
5.3.5Termination of Study
6Study Intervention/Investigational Product
6.1Study Product Description
6.1.1Acquisition
6.1.2Formulation, Packaging, and Labeling
6.1.3Product Storage and Stability
6.2Dosage, Preparation and Administration of Study Intervention/Investigational Product
6.3Modification of Study Intervention/Investigational Product for a Participant
6.4Accountability Procedures for the Study Intervention/Investigational Product(s)
6.5Assessment of Subject Compliance with Study Intervention/Investigational Product
6.6Concomitant Medications/Treatments
7Study Schedule
7.1Screening
7.2Enrollment/Baseline
7.3Follow-up
7.4Final Study Visit
7.5Early Termination Visit
7.6Unscheduled Visit
8Study Procedures/Evaluations
8.1Clinical Evaluations
8.2Laboratory Evaluations
8.2.1Clinical Laboratory Evaluations
8.2.2Special Assays or Procedures
8.2.3Specimen Preparation, Handling, and Shipping
9Assessment of Safety
9.1Specification of Safety Parameters
9.2Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
9.2.1Adverse Events
9.2.2Reactogenicity (for Vaccine Studies and Some Therapeutic Trials)
9.2.3Serious Adverse Events
9.2.4Procedures to be Followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical Findings
9.3Reporting Procedures
9.3.1Serious Adverse Events
9.3.2Regulatory Reporting for Studies Conducted Under DMIDSponsored IND
9.3.3Regulatory Reporting for Studies Not Conducted Under DMIDSponsored IND
9.3.4Other Adverse Events (if applicable)
9.3.5Reporting of Pregnancy
9.4Type and Duration of Follow-up of Subjects after Adverse Events
9.5Halting Rules
9.6Safety Oversight (ISM plus SMC or DSMB)
10Clinical Monitoring
10.1Site Monitoring Plan
11Statistical Considerations
11.1Study Hypotheses
11.2Sample Size Considerations
11.3Planned Interim Analyses (if applicable)
11.3.1Safety Review
11.3.2Immunogenicity or Efficacy Review
11.4Final Analysis Plan
12Source Documents and Access to Source Data/Documents
13Quality Control and Quality Assurance
14Ethics/Protection of Human Subjects
14.1Ethical Standard
14.2Institutional Review Board
14.3Informed Consent Process
14.3.1Informed Consent/Assent Process (in Case of a Minor)
14.4Exclusion of Women, Minorities, and Children (Special Populations)
14.5Subject Confidentiality
14.6Study Discontinuation
14.7Future Use of Stored Specimens
15Data Handling and Record Keeping
15.1Data Management Responsibilities
15.2Data Capture Methods
15.3Types of Data
15.4Timing/Reports
15.5Study Records Retention
15.6Protocol Deviations
16Publication Policy
17Literature References
Supplements/Appendices
Appendix A: Schedule of Events
List of Abbreviations
AE / Adverse Event/Adverse ExperienceCFR / Code of Federal Regulations
CIOMS / Council for International Organizations of Medical Sciences
CONSORT / Consolidated Standards of Reporting Trials
CRF / Case Report Form
CRO / Contract Research Organization
DCC / Data Coordinating Center
DHHS / Department of Health and Human Services
DMID / Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS
DSMB / Data and Safety Monitoring Board
eCRF / Electronic Case Report Form
FDA / Food and Drug Administration
FWA / Federalwide Assurance
GCP / Good Clinical Practice
HIPAA / Health Insurance Portability and Accountability Act
IB / Investigator’s Brochure
ICF / Informed Consent Form
ICH / International Conference on Harmonisation
ICMJE / International Committeeof Medical Journal Editors
IDE / Investigational Device Exemption
IEC / Independent or Institutional Ethics Committee
IND / Investigational New Drug Application
IRB / Institutional Review Board
ISM / Independent Safety Monitor
JAMA / Journal of the American Medical Association
MedDRA / Medical Dictionary for Regulatory Activities
MOP / Manual of Procedures
N / Number (typically refers to subjects)
NCI / National Cancer Institute, NIH, DHHS
NDA / New Drug Application
NEJM / New England Journal of Medicine
NIAID / National Institute of Allergy and Infectious Diseases, NIH, DHHS
NIH / National Institutes of Health
OCRA / Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS
OHRP / Office for Human Research Protections
OHSR / Office for Human Subjects Research
ORA / Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS
PHI / Protected Health Information
PI / Principal Investigator
PK / Pharmacokinetics
QA / Quality Assurance
QC / Quality Control
SAE / Serious Adverse Event/Serious Adverse Experience
SMC / Safety Monitoring Committee
SOP / Standard Operating Procedure
US / United States
WHO / World Health Organization
Please modify list to include your protocol-specific terms.
Protocol Summary
Limit to 1-2 pages
Put key words in boldface in Protocol Summary.
Phase: / I, II, III, IV
Population: / Include sample size, gender, age, general health status, geographic location
Number of Sites: / 3 or fewer, list here; otherwise, list only in Section1
Study Duration: / Provide time from when the study opens until the monitor completes the close out visit.
Subject Participation Duration: / Provide time it will take to conduct the study for each individual participant.
Description of Agent or Intervention: / Include dose and route of administration
Objectives: / Copy objectives and clinical/laboratory outcome measures from the appropriate sections of the protocol. Include primary/secondary outcome measures and method by which outcome will be determined.
Primary:
Secondary:
Description of Study Design: / This schematic should provide an overview of the study design, including study arms, sample size and schedule of interventions (e.g., vaccine administration), if applicable; a detailed schematic describing all visits and assessments (schedule of events) will be included in Appendix A.
Estimated Time to Complete Enrollment:
*Schematic of Study Design:
Example #1: Table format (e.g., dose escalation)
Cohort A / ARM 1 / Sample Size / Intervention 1ARM 2 / Sample Size / Intervention 2
Instructions for progressing to next phase (if applicable):
Cohort B / ARM 1 / Sample Size / Intervention 1ARM 2 / Sample Size / Intervention 2
Example #2: Flow diagram
Prior to
Enrollment
Time Point or
Study Visit 1
Time Point or
Study Visit 2
Time Point or
Study Visit 3
Time Point
or Study Visit …
*This schematic study design may be modified to include 3 arms or your protocol-specific design.
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1
DMID Interventional Protocol TemplateVersion 5.0
25 March 2011
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1Key Roles
Refer to ICH E6, Section 6.1
(
For questions regarding this protocol, contact <insert name of appropriate DMID staff> at <NIAID/DMID (insert contact information)>.
Individuals: / Protocol Champion: Division of Microbiology and Infectious Diseases (DMID) official authorized to sign the protocol and protocol amendments on behalf of the Protocol Team:Provide the following information for each individual:
Name, degree, title
Institution Name
Address
Phone Number
Fax Number
Principal Investigator: Site investigator responsible for conducting the study
Medical Monitor: (if applicable)
Institutions: / Study sites, clinical laboratory(ies), and other medical or technical departments and/or institutions, as applicable.
Provide the following information for each organization or institution:
Institution Name
Address
Contact Person/Local Investigator
Phone Number
Fax Number
Optional: / Consider listing, for example:
Major international collaborators, if not included as site investigators
Protocol data manager, epidemiologist, statistician
DMID clinical affairs specialist
Industry representative(s)
Other individuals should be listed in a separate document (e.g., the Manual of Procedures [MOP]) as appropriate
Institutional Review Board (IRB) contact information
2Background Information and Scientific Rationale
2.1Background Information
Refer to ICH E6, Section 6.2
()
Include:
The name and description of the study intervention/investigational products(s)
A summary of findings from nonclinical in vitro or in vivo studies that have potential clinical significance
A summary from relevant clinical trials
Discussion of important literature and data that are relevant to the trial and that provide background for the trial (reference citations are listed in Section 17)
Applicable clinical, epidemiological, or public health background or context of the study
Importance of the study and any relevant treatment issues or controversies
2.2Rationale
Include a description of and justification for the route of administration, dosage, dosing regimen, intervention periods, and selection of study population. Include a statement of the hypothesis.
2.3Potential Risks and Benefits
Refer to 45 CFR Part 46.116 (a) (2) and (3)
().
Include a discussion of known risks and benefits, if any, to human subjects.
2.3.1Potential Risks
Include a review of relevant literature, which should be referenced. Add relevant websites, etc from which the information could be drawn.
If a package insert is available, it should be used as the primary source of risk information. If the product is investigational, the Investigator’s Brochure (IB) should be the primary source of the risk information. In addition, literature searches can also provide relevant risk information. If the risk profile cannot be described from any of the above sources, the risk information discussion will result from the literature search and review.
Describe in detail any physical, psychological, social, legal, economic, or any other risks to subjects that the Principal Investigator (PI) foresees, as to each of the following:
Immediate risks
Long-range risks
Rationale for the necessity of such risks
Alternative data gathering procedures that have been considered or will be considered
Why alternative procedures may not be feasible
Why the value of the information to be gained outweighs the risks involved.
2.3.2Known Potential Benefits
If the research is beneficial, describe in detail any physical, psychological, social, legal, economic, or any other benefits to subjects that the PI foresees.
Note: Payment to subjects, whether as an inducement to participate or as compensation for pain and inconvenience, is not considered a “benefit.”
3Objectives
3.1Study Objectives
A detailed description of the primary and secondary objectives of the study is included in this section. These typically include:
Statement of purpose, e.g., to assess, to determine, to compare, to evaluate
General purpose, e.g., efficacy, safety, immunogenicity, pharmacokinetics
Specific purpose, e.g., dose-response, superiority to placebo
Name(s) of intervention (e.g., vaccine, drug, biologic) being evaluated, specification of doses or dose ranges to be studied, dose regimens
3.2Study Outcome Measures
Refer to ICH E6, Sections 6.7-6.8
(
This section should include the methods for assessing how the objectives are met, i.e., the study outcome measures.
An outcome measure is “an observation variable recorded for [subjects] in the trial at 1 or more time points after enrollment for the purpose of assessing the effects of the study treatments” (Meinert CL. Clinical trials: design, conduct, and analysis. Oxford: Oxford University;1986). Give succinct but precise definitions of the outcome measures used to measure the primary and key secondary outcomes stated in the study objectives, including the study visits at which the samples will be obtained and the specific laboratory tests to be used.
3.2.1Primary Outcome Measures
Outcome measures should be prioritized. Generally, there should be just 1 primary variable, with evidence that it will provide a clinically relevant, valid, and reliable measure of the primary objective (e.g., laboratory procedures, safety assays).
3.2.2Secondary Outcome Measures
Secondary outcome measures should be included, whether or not they add information about the primary objective or address secondary objectives. Discuss their importance and role in the analysis and interpretation of study results.
4Study Design
Refer to ICH E6, Section 6.4
(
The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should include:
A description of the type/design of trial to be conducted (e.g., placebo-controlled, double-mask, parallel design, open-label, dose-escalation, dose-ranging)
A description of the study population (e.g., healthy/sick, inpatient/outpatient)
The rationale for design features should be discussed
Phase of trial
Single or multicenter
The number of study groups/arms
Description of study groups/arms including sample size (including a table, if appropriate)
Approximate time to complete study enrollment
The expected duration of subject participation
Identification of the test agent and specifics of administration of other agents (e.g., placebo)
A description of the sequence and duration of all trial periods, including follow-up (specify individual subjects vs entire trial)
Changes in scheduling, such as dose escalation
Any stratifications
A specific statement of the primary and secondary outcomes to be measured during the trial (must be consistent with Study Objectives, as stated in Section 3)
Methods for collecting data for assessment of study objectives
Other protocol-specific details, such as centralization of evaluations (e.g., central laboratory or central reading center for clinical scans)
Interim analysis plans
Identify structure for safety oversight per DMID guidelines (e.g., Data and Safety Monitoring Board (DSMB), Safety Monitoring Committee (SMC), and/or Independent Safety Monitor (ISM), and DMID medical monitor). Ensure consistency with Section 9.6. For DMID guidelines refer to: .
4.1Substudies (if applicable)
Definition: A substudy asks a separate research question from the parent protocol and may or may not contribute to the parent protocol’s objectives but uses all or a subset of study participants or specimens.
Note that substudies do not have full protocols but rather are incorporated into the main protocol.
A concept sheet for a proposed substudy must be approved by the DMID Project Officer/Program Officer. Once the concept for a substudy is approved by the Program Officer, a decision must be made by DMID, in conjunction with the investigator, whether the concept is appropriate as a substudy or should be a stand-alone study.
List with brief description:
Description of the substudy and its objectives
Impact on main study
Potential participating sites
Behavioral issues
If substudy is added to an ongoing study, a protocol amendment is required.
5Study Enrollment and Withdrawal
The study population and inclusion/exclusion criteria should be clearly defined in this section of the protocol.
The study population should be commensurate with the stage of the study and the development stage for the study product. This section should include a discussion of recruitment strategies, specifically for achieving NIH gender/minority guidelines.
If the study intends to enroll children, pregnant women, prisoners, or other vulnerable populations, refer to applicable section of 45 CFR Part 46 Subpart B – Additional Protections Pertaining to Research, Development and Related Activities Involving Fetuses, Pregnant Women, and Human In Vitro Fertilization (45 CFR Part 46.201-46.211); Subpart C – Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects (45 CFR Part 46.301-46.306); Subpart D – Additional Protections for Children Involved as Subjects in Research (45 CFR Part 46.401-409). Please refer to these regulations and Office for Human Research Protections (OHRP) guidelines when choosing the study population.
Note that these regulations apply if any subjects are members of the designated population even if it is not the target population. For example, if a subject becomes a prisoner during the study. Refer to: ; and .
Provide the target sample size, including actual numbers to be enrolled.
- Include numbers of women, minorities, and children expected to be recruited. If women, minorities, or children will not be recruited, explain why not. Provide justification for Exclusion in Ethics/Protection of Human Subjects, Section 14.4.
Refer to: .
Indicate from where the study population will be drawn (e.g., inpatient hospital setting, outpatient clinics, student health service, or general public). Where appropriate (singlecenter studies), include names of hospitals, clinics, etc.
Identify strategies for subject recruitment and retention.
If subjects require screening: distinguish between screening subjects (e.g., discussing the study with them) vs enrolling subjects (e.g., obtaining informed consent and obtaining samples).